This R01 application proposes a genome-wide association study (GWAS) to probe the hereditary basis for risk or resilience to develop post-traumatic stress disorder (PTSD). Little information is available about factors that explain why some trauma survivors develop stress disorders (up to 15%) and others do not. However, recovery from trauma may be impacted by a web of risk and resilience factors, indexed by genetic, psychological, social/cultural, and biological systems. The goal of this project is to identify such factors by a) studying a prospectively assessed, systematically phenotyped population to discover factors that predict development of PTSD and b) indentifying gene-by-environment interactions. The San Diego Marine Resiliency Study (MRS) is an ongoing, prospective study of >2500 US Marines bound for combat deployment to Iraq or Afghanistan, with the goal to identify factors that predict development of PTSD. Each Marine is evaluated pre-deployment on an array of psychosocial, psychophysiological, and biophysiological phenotypes, and then followed by longitudinal assessments post-deployment. The phenotypes collected were chosen for their potential to serve as 'intermediate'phenotypes for stress-triggered disorders, and include for example startle reactivity, heart rate/blood pressure, and markers of HPA function and catecholamine signaling. Information on environmental risk factors such as past trauma and childhood neglect are collected to identify common experiences that may influence PTSD development. The MRS is thus uniquely suited to identify both genetic and environmental contributions to PTSD symptom development. Data collection of the MRS is funded by the DoD and VA, and will be completed at the start of this proposed funding period, but R01 funding is essential for the implementation of the as-yet un-funded genetic component. The overall guiding hypothesis is that genomic variations give rise to risk/susceptibility traits that, when actuated by the appropriate environmental stimulus, such as combat, give rise to PTSD and other stress- triggered phenotypes. Specifically, this application aims to: 1) Scan the entire genome of ~2500 combat- exposed subjects for genetic variants, 2) Examine the association of genetic variants with PTSD scores, and test for gene-by-environment interactions including combat and other trauma exposure, 3) Test for association of genetic variants with simpler biological traits linked to PTSD vulnerability and its longitudinal changes over time, and thus to build and test genetic risk scores, and 4) Fine-map and replicate findings in other cohorts. We anticipate that the insights gained from this multi-faceted approach will provide a unique opportunity to improve understanding of the genetic contributors to PTSD, and open the way towards novel diagnostic tests and therapeutic approaches to this currently enigmatic and difficult-to-manage condition. Importantly, genome- wide genotype data of a large PTSD cohort is not yet publicly available, and this study thus will generate a rich resource for research on genetic and environmental effects for the neuropsychiatric research community. PUBLIC HEALTH RELEVANCE: Post-traumatic stress disorder (PTSD) poses not only individual suffering, but also a significant burden on the US health care system, with rates to develop PTSD after combat and other trauma exposure around 10-15%. PTSD affects only some of those exposed to trauma, and vulnerability factors are poorly understood. This R01 application seeks to determine genetic contributions to and predictors of the clinical outcome of PTSD, and thus to pave the way for novel diagnostic tests and therapeutic approaches to this difficult-to-manage disorder.